Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome

Witztum, Joseph L.; Gaudet, Daniel; Freedman, Steven D.; Alexander, Veronica J.; Digenio, Andrés; Williams, Karren; Yang, Qingqing; Hughes, Steven G.; Geary, Richard S.; Arca, Marcello; Stroes, Erik S.G.; Bergeron, Jean; Soran, Handrean; Civeira, Fernando; Hemphill, Linda; Tsimikas, Sotirios; Blom, Dirk; O’Dea, Louis; Bruckert, Éric

doi:10.1056/nejmoa1715944

Cited by 435 publications

(296 citation statements)

References 33 publications

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“…Volanesorsen is an antisense inhibitor of APOC3 synthesis which lowers plasma APOC3 and triglyceride levels. Use of volanesorsen has been associated with significant reduction in triglyceride levels in patients with familial hyperchylomicronaemia (28), though the efficacy and safety for its use during pregnancy remains to be seen.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic plasma exchange for the management of severe gestational hypertriglyceridaemic pancreatitis due to lipoprotein lipase mutation

Kim

Hakeem

Abdullah

et al. 2020

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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Summary A 19-year-old female presented at 25-weeks gestation with pancreatitis. She was found to have significant hypertriglyceridaemia in context of an unconfirmed history of familial hypertriglyceridaemia. This was initially managed with fasting and insulin infusion and she was commenced on conventional interventions to lower triglycerides, including a fat-restricted diet, heparin, marine oil and gemfibrozil. Despite these measures, the triglyceride levels continued to increase as she progressed through the pregnancy, and it was postulated that she had an underlying lipoprotein lipase defect. Therefore, a multidisciplinary decision was made to commence therapeutic plasma exchange to prevent further episodes of pancreatitis. She underwent a total of 13 sessions of plasma exchange, and labour was induced at 37-weeks gestation in which a healthy female infant was delivered. There was a rapid and significant reduction in triglycerides in the 48 h post-delivery. Subsequent genetic testing of hypertriglyceridaemia genes revealed a missense mutation of the LPL gene. Fenofibrate and rosuvastatin was commenced to manage her hypertriglyceridaemia postpartum and the importance of preconception counselling for future pregnancies was discussed. Hormonal changes in pregnancy lead to an overall increase in plasma lipids to ensure adequate nutrient delivery to the fetus. These physiological changes become problematic, where a genetic abnormality in lipid metabolism exists and severe complications such as pancreatitis can arise. Available therapies for gestational hypertriglyceridaemia rely on augmentation of LPL activity. Where there is an underlying LPL defect, these therapies are ineffective and removal of triglyceride-rich lipoproteins via plasma exchange should be considered. Learning points: Hormonal changes in pregnancy, mediated by progesterone,oestrogen and human placental lactogen, lead to a two- to three-fold increase in serum triglyceride levels. Pharmacological intervention for management of gestational hypertriglyceridaemia rely on the augmentation of lipoprotein lipase (LPL) activity to enhance catabolism of triglyceride-rich lipoproteins. Genetic mutations affecting the LPL gene can lead to severe hypertriglyceridaemia. Therapeutic plasma exchange (TPE) is an effective intervention for the management of severe gestational hypertriglyceridaemia and should be considered in cases where there is an underlying LPL defect. Preconception counselling and discussion regarding contraception is of paramount importance in women with familial hypertriglyceridaemia.

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Section: Discussionmentioning

confidence: 99%

Therapeutic plasma exchange for the management of severe gestational hypertriglyceridaemic pancreatitis due to lipoprotein lipase mutation

Kim

Hakeem

Abdullah

et al. 2020

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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“…With long-term DFFP treatment, the frequency of HTG-associated complications was markedly reduced in both patients. Antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen represents a novel pharmacological option to lower TG levels for the very rare patients with confirmed monogenic FCS and failure of a strict low-fat diet, which has been investigated in phase 3 clinical trials, but longterm experience in routine care is not available [36]. Thrombocytopenia and injection-site reactions were reported as common adverse events [36].…”

Section: Htg-apmentioning

confidence: 99%

Relapsing and Progressive Complications of Severe Hypertriglyceridemia: Effective Long-Term Treatment with Double Filtration Plasmapheresis

Grupp¹,

Beckermann²,

Köster³

et al. 2020

Blood Purif

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Background: Severe hypertriglyceridemia (HTG) is associated with major complications such as acute or relapsing pancreatitis (AP) and atherosclerotic cardiovascular disease (ASCVD). Rapid elimination of triglyceride (TG)-rich lipoproteins (LP) with double filtration plasmapheresis (DFPP) without need for substitution has been found to be effective for the acute, short-term treatment of HTG-induced AP. Data on the long-term use of DFPP to prevent HTG-associated complications are scarce. Objectives: To evaluate the use and efficacy of regular DFPP treatment in clinical practice for preventing recurrence of HTG-associated complications in thera py refractory patients. Methods: Retrospective multicenter study in patients with severe symptomatic drug and diet refractory HTG with regular DFPP treatment. Patients' incidence of HTG-associated pancreatic or cardiovascular complications was compared before treatment and with regular DFPP treatment. Results: Ten patients (3 female) were identified with baseline maximal TG concentrations of 2,587-28,090 mg/dL (median 5,487 mg/dL; interquartile range [IQR] 4,340-12,636). The mean observation period was 3.9 ± 3.4 years before and 3.8 ± 3.0 years after commencement of DFPP. In 5 patients, severe HTG was related to chylomicronemia, 2 patients had familial partial lipodystrophy Dunnigan, and 1 patient had additional LP(a)-hyperlipoproteinemia. The main HTG-associated complication was recurrent AP in 8 patients, including 1 patient treated during pregnancy. Two patients presented severe progressive ASCVD. With long-term DFPP treatment, the annual rate of HTGassocia ted pancreatic or cardiovascular complications declined from median 1.4 (IQR 0.7-2.6) to 0 (IQR 0.0-0.4; p < 0.005). The absolute number of events was reduced by 77%. In 6 patients (60%) episodes of AP did not occur, nor was progression of ASCVD detected clinically or by routine imag-Grupp et al.

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“…The main adverse effects included injection-site reactions, thrombocytopenia, and abdominal pain, an event that seems paradoxical in the context of the disease clinical manifestations. 26 Our patient might not benefit from this therapy taking into account the lack of solid evidence for treating HTG caused by APOC2 mutations and current TG levels <500 mg/dL.…”

Section: Discussionmentioning

confidence: 86%

“…Volanesorsen is a novel therapeutic option, not available in Colombia, that induces an antisense-mediated inhibition of hepatic APOC3 mRNA and decreases apolipoprotein C-III (ApoC-III) levels which, among other effects, favors LPL function. 8,26 The APPROACH, a randomized clinical trial conducted by Witztum and colleagues in FCS patients treated with volanesorsen, showed a significant reduction of 84% and 77% in ApoC-III and TG at 90 days. Nevertheless, only one patient with APOC2 mutation was enrolled in the trial.…”

Section: Discussionmentioning

confidence: 99%

<p>A Novel APOC2 Mutation in a Colombian Patient with Recurrent Hypertriglyceridemic Pancreatitis</p>

Pinilla-Monsalve

Lores

Pachajoa

et al. 2020

TACG

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Hypertriglyceridemia is a common disease with only 2% of cases exhibiting monogenic mutations. Familial chylomicronemia syndrome (FCS) is a rare genetic condition associated with recurrent and severe episodes of pancreatitis and is mainly caused by mutations in the LPL gene, with few cases related to abnormal function of apolipoprotein C-II. This is a 50-year-old female with a past medical history of arterial hypertension, miscarriage and recurrent pancreatitis. In the last four years, her triglycerides and lipase concentration reached >3000 mg/dL and >700 U/L, respectively. The patient was not responsive to statins, fibrates, or tetrahydrolipstatin. A novel homozygous frameshift mutation on exon 3 of the APOC2 gene was detected, c.133_134delTC. Subsequent Sanger sequencing confirmed that three first-degree relatives were carriers of the same mutation. To the best of our knowledge, we are reporting the first Colombian patient with FCS due to an APOC2 mutation. We propose that this mutation caused recurrent hypertriglyceridemic pancreatitis.

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Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome

Cited by 435 publications

References 33 publications

Therapeutic plasma exchange for the management of severe gestational hypertriglyceridaemic pancreatitis due to lipoprotein lipase mutation

Therapeutic plasma exchange for the management of severe gestational hypertriglyceridaemic pancreatitis due to lipoprotein lipase mutation

Relapsing and Progressive Complications of Severe Hypertriglyceridemia: Effective Long-Term Treatment with Double Filtration Plasmapheresis

<p>A Novel APOC2 Mutation in a Colombian Patient with Recurrent Hypertriglyceridemic Pancreatitis</p>

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